Method of coating a catheter

ABSTRACT

CATHETERS ARE PROVIDED WITH COATING OF A HYDROPHILIC ACRYLATE OR METHACRYLATE POLYMER. THE COATING REDUCES THE IRRITATION AND INFECTION NORMALLY ACCOMPANYING THE USE OF CATHETERS. INFECTION CAN BE REDUCED STILL FURTHER BY ABSORBING AN ANTIBIOTIC IN THE COATING.

Oct 1972 T. H. SHEPHERD ErAL 3,695,921

METHOD OF COATING A CATHETER Original Filed Aug. 15. 1968 v INVENTORSiwms 15? 152 582 2%(7-5 Z, 2043 /Q/ ATTORNEYS United States Patent U.S.Cl. 117-72 14 Claims ABSTRACT OF THE DISCLOSURE Catheters are providedwith coating of a hydrophilic acrylate or methacrylate polymer. Thecoating reduces the irritation and infection normally accompanying theuse of catheters. Infection can be reduced still further by absorbing anantibiotic in the coating.

The present application is a continuation-in-part of application Ser.No. 654,044, filed July 4, 1967; application Ser. No. 650,259, filedJune 30, 1967 and now abandoned; and application Ser. No. 567,856, filedJuly 26, 1966 and now Pat. 3,520,949, issued July 21, 1970 and is adivision of application 752,221, filed Aug. 13, 1968, now Pat.3,566,874, March 2, 1971.

The present invention relates to coated catheters and to bindinghydrophilic polymers to rubber.

One of the problems normally encountered in the use of catheters is therisk of infection.

It is an object of the present invention to reduce the danger ofinfection which frequently occurs in the use of catheters.

Another object is to bond hydrophilic polymers to rubber and similarmaterials.

Still further objects and the entire scope of applicability of thepresent invention will become apparent from the detailed descriptiongiven hereinafter; it should be understood, however, that the detaileddescription and specific examples, while indicating preferredembodiments of the invention, are given by way of illustration only,since various changes and modifications within the spirit and scope ofthe invention will become apparent to those skilled in the art from thisdetailed description.

It has now been found that these objects can be attained by coating acatheter with hydrophilic acrylate and methacrylate polymer. The use ofthe acrylate or methacrylate polymer by itself is effective inpreventing infections. Even better results in reducing infection areobtained if the polymer is impregnated with an antibiotic or germicide.

The present invention is useful with either cannulae catheters orureteral catheters. The ureteral catheters are normally made of naturalrubber but can be made of synthetic rubbers, e.g. poly cis isoprene,butadiene-styrene copolymer, butyl rubber, silicone rubber, e.g. polydimethyl siloxane, neoprene (polychloroprene).

The cannulae catheters can be made of the same kinds of materials or ofpolyvinyl chloride.

The coating of the hydrophilic acrylate or methacrylate is normallyapplied by dipping the catheter in a casting syrup of the monomer orpartially polymerized monmer and then completing the polymerization. Athicker coating can be obtained by dipping this coated product again ina casting syrup and polymerizing. Preferably the undercoat is crosslinked since it has been found that the uncross-linked hydrophilicacrylates and methacrylates do not adhere well to rubber or the likealthough they will 3,695,921 Patented Oct. 3, 1972 adhere well to across-linked copolymer which has been applied as a coating to therubber. The monomer or partial polymer casting syrup wherein a crosslinking agent is employed penetrates the rubber and swells it slightly.The casting syrup is then polymerized while the rubber is in the swollencondition. As stated more polymerizable hydrophilic material can bebonded to this to build up the thickness. The second coating ofhydrophilic material need not be the same as the undercoat.

To increase the effectiveness against infection the coated catheter(either with a single or plural coating of hydrophilic polymer) isimmersed in a solution of an antibiotic or germicide. The antibiotic orgermicide is then retained by the hydrophilic coating even if thesolvent is removed. If the antibiotic or germicide is sufficiently heatstable it can be added to the casting syrup and thus be incorporated inthe product when the hydrophilic material is polymerized. However mostantibiotics are not sufiiciently heat stable to permit such technique.

Examples of suitable antibiotics; and germicides which can be usedinclude penicillin, neomycin, sulfate, cephtalothin (Keflin),Bacitracin, phenoxymethyl, penicillin, lincoymycin hydrochloride,sulfadiazine, methyl sulfadiazine, succinoylsulfathiazole,phthalylsulfathiazole, sulfacetamide, procaine penicillin, streptomycin,aureomycin, terramycin, quaternary ammonium halides, e.g. trimethylbenzyl ammonium chloride, cetyl pyridinium chloride, triethyl dodecylammonium bromide, hexachlorophene.

The hydrophilic monomer employed is preferably a hydroxy lower alkylacrylate or methacrylate, hydroxy lower alkoxy lower alkyl acrylate ormethacrylate, e.g. 2-hydroxyethyl acrylate, Z-hydroxyethyl methacrylate,diethylene glycol monomethacrylate, diethylene glycol monoacrylate,2-hydroxypropyl acrylate, 2-hydroxypropyl methacrylate, 3-hydroxypropylacrylate, 3-hydroxypropyl methacrylate, dipropylene glycolmonomethacrylate.

In preparing hydroxyalkyl monoacrylates and methacrylates a small amountof the diacrylate of dimethacrylate is also formed. This need not beremoved and in fact its presence is frequently helpful in formingcoatings which adhere securely to the catheter.

When cross-linked hydrophilic polymers are prepared preferably the crosslinking agent is present in an amount of 0.1 to 2.5%, most preferablynot over 2.0%, although up to 15% or even 20% of cross-linking agent canbe used. Typical examples of cross-linking agents includecopolymerizable polyethylenically unsaturated compounds, e.g. ethyleneglycol diacrylate, ethylene glycol dimethacrylate, -1,2-butylenedimethacrylate, 1,3-butylene dimethacrylate, 1,4-butylenedimethacrylate, propylene glycol diacrylate, propylene glycol.diacrylate, diethylene glycol dimethacrylate, dipropylene glycoldimethacrylate, diethylene glycol diacrylate, dipropylene glycol diacrylate, divinyl benzene, divinyl toluene, diallyl tartrate, allylpyruvate, allyl malate, divinyl tartrate, triallyl melamine,N,N-methylene bis acrylamide, glycerine trimethacrylate, diallylmaleate, divinyl ether, diallyl monoethylene glycol citrate, ethyleneglycol vinyl allyl citrate, allyl vinyl maleate, diallyl itaconate,ethylene glycol diester of itaconic acid, divinyl sulfone,hexahydro-l,3,5-triacry ltriazine, triallyl phosphite, diallyl ester ofbenzene phosphonic acid, polyester of maleic anhydride with triethyleneglycol, polyallyl glucose, e.g. triallyl glucose, polyallyl sucrose,e.g. pentaallyl sucrose, sucrose diacrylate, glucose dimethacrylate,pentaerythritol tetraacrylate, sorbitol dimethacrylate, diallylaconitate, divinyl citraconate, diallyl fumarate.

Unless otherwise indicated all parts and percentages are by weight.

As catalysts for carrying out the polymerization there is employed afree radical catalyst in the range of 0.05 to 1% of the polymerizablehydroxyal kyl ester or the like. The preferred amount of catalyst is 0.1to 0.2% of the monomer. Usually only a portion of the catalyst, e.g. 20%is added initially to the monomer and the balance is added to thecasting syrup after partial polymerization. Typical catalysts includet-butyl peroctoate, benzoyl peroxide, isopropyl percarbonate, methylethyl ketone peroxide, cumene hydroperoxide, and dicumyl peroxide.Irradiation, e.g., by ultra violet light or gamma rays, also can beemployed to catalyze the polymerization. Polymerization can be done at20 to 150 C., usually 40 to 90 C.

The invention will be understood best in connection with the drawingswherein:

FIG. 1 is a longitudinal view of a ureteral catheter treated accordingto the invention;

FIG. 2 is a sectional view along the line 22 of FIG. 1; and

FIG. 3 is a sectional view of a catheter similar to that of FIG. 1 butwherein an antibiotic is incorporated in the coating.

Referring more specifically to FIGS. 1 and 2 of the drawings there isprovided a conventional constant drainage indwelling Foley ureteralcatheter 10 made of natural rubber. It has an inner closure end portion12 provided in opposite thereof with opposed ports 14 which cornmunicatewith the axial passage or lumen 16 that is co extensive in length withthe length of the catheter. The outer end 18 of the catheter 10 is openand of larger diameter than the main flexible body of the catheter. Aninflatable retaining bag or balloon 20 encompasses the tube 22 of thecatheter at a point inwardly of ports or openings 14. and is sealed orotherwise connected thereto in conventional fashion. A longitudinallyextending small air tube 24 and indicated by the dotted line in FIG. 1is positioned within the catheter and communicates at its inner endthrough a lateral opening (not shown) in the Wall of the catheter withthe interior of the inflatable bag 20. The air tube 24 has an outwardlyextending lateral valve end portion or arm 26 that projects from oneside of the catheter and terminates in a flared tubular portion 28.

The Foley catheter 10 is immersed in a casting syrup which contains apartial polymer of 98.5% Z-hydroxyethyl methacrylate and 1.5% ofethylene glycol dimethacrylate. The catheter is immersed with tip end 12down to a depth within 2 inches of the valve branch 30. The catheter isthen removed, allowed to drain and the coating cured in an oven to forminner coating layer 32. The coated portion of the catheter is indicatedby the arrows in FIG. 1. In addition to the coating on the outside ofthe catheter, there is a similar coating formed on the inside of thecatheter as a result of the syrup entering at the ports 14.

After coating layer 32 is cured the catheter is dipped again in thecasting syrup, remolved therefrom and the new outer coating layer 34cured.

FIG. 3 shows a Foley catheter similar to that illustrated in FIGS. 1 and2. However, after the coating 34 is cured the catheter is immersed in anantibiotic soultion, e.g. aqueous penicillin, and dried so thatpenicillin 36 is retained homogeneously distributed in the coatinglayers 32 and 34.

Typical examples of casting syrups suitable for coating catheters areset forth in Examples 1-17 below.

EXAMPLE 1 A solution was made of 100 parts of 2-hydroxyethy1 acrylate,0.2 part of ethylene glycol dimethacrylate and 0.4 part of t-butylperoctoate.

EXAMPLE 2 A solution was made of 100 parts of an isomeric mixture ofhydroxyisopropy-l methacrylates, 0.2 part propylene glycoldimethacrylate and 0.4 part of t-butyl peroctoate.

EXAMPLE 3 parts of Z-hydroxyethyl methacrylate was stirred with 0.05part of t-butyl peroctoate in a nitrogen atmos phere at a temperature of40 C. for 30 minutes. The resultant mixture was cooled to 25 C. andt-butyl peroctoate added so as to make the total amount of tbutylperoctoate added in the system 0.15 part. 0.1 part of ethylene glycoldimethacrylate was also added along with the second addition of thet-butyl peroctoate.

EXAMPLE 4 The process of Example 3 was repeated, substituting 0.2 partof 1,3-butylene glycol dimethacrylate in place of the ethylene glycoldimethacrylate as the cross linking monomer.

EXAMPLE 5 100 parts of 2-hydroxyethylmethacrylate was stirred with 50parts of distilled water and 0.1 part of t-butyl peroctoate in ananaerobic atmosphere at a temperature of 40 C. for 20 minutes. Theresultant mixture was cooled to 25 C. and 0.05 part of t-butylperoctoate added and at the same time there was added 0.2 part ofethylene :glycol dimethacrylate as a cross linking monomer.

EXAMPLE 6 The process of Example 5 was repeated in the absence of water,to give a casting syrup.

EXAMPLE 7 The process of Example 6 was repeated but the initial catalystconsisted of a mixture of 0.05 part t-butyl peroctoate and 0.1 part ofisopropyl percarbonate. The added catalyst was 0.05 part of isopropylpercarbonate.

EXAMPLE 8 EXAMPLE 9 The process of Example 8 was followed, substitutinghydroxypropyl methacrylate for the Z-hydroxyethyl methacrylate.

EXAMPLE 10 The process of Example 8 was followed using isopropylpercarbonate as the catalyst and substituting 1,3-butylene tglycoldimethacrylate for the ethylene glycol dimethacrylate as the crosslinking monomer.

EXAMPLE 11 Suitably purified Z-hydroxyethyl methacrylate was stirredwith 0.15 gram of isopropyl percarbonate in an anaerobic atmosphere atambient temperature. Ethylene glycol dimethacrylate in the concentrationof 0.1 gram per 100 grams of 2-hydroxyethyl methacrylate was added.

EXAMPLE 12 100 parts of Z-hydroxyethyl methacrylate was stirred with0.05 part t-butyl peroctoate in a nitrogen atmosphere at a temperatureof 30 C. for 30 minutes. The resultant mixture was cooled to 25 C. andadditional peroctoate added to make up a total of 0.15 part, there beingadded at the same time 0.1 part of ethylene glycol dimethacrylate.

EXAMPLE 13 100 grams of 2-hydroxyethyl methacrylate was mixed with 0.20gram of t-butyl peroctoate in an inert atmosphere and 0.20 gram ofethylene glycol dimethacrylate was added.

EXAMPLE 14 100 grams of 2-hydroxyethyl methacrylate was stirred with 0.1gram of t-butyl peroctoate and 0.15 gram of ethylene glycoldirnethacrylate was added.

EXAMPLE 15 100 grams of purified 2-hydroxyethyl methacrylate was mixedwith 15 grams of ethylene glycol dimethacrylate and 0.3 gram of t-butylperoctoate.

EXAMPLE 16 In a 5 gallon resin kettle there was placed kilograms ofZ-hydroxyethyl methacrylate, 150 grams of ethylene glycol dimethacrylateand 4.0 grams of t-butyl peroctoate. The kettle was heated to 95 C. withstirring over a 50 minute period, whereupon the reaction mixture wasrapidly cooled, yielding a syrup having a viscosity of 420 centipoisesat 30 C. To the syrup was added 20 grams of ethylene glycoldimethacrylate and 20 grams of t butyl peroctoate, and the syrup wasstirred until a homogenous solution was obtained.

This syrup was useful in coating both ureteral and cannulae cathetersmade of rubber and other flexible polymers. Among the cannulae catheterswere Levine tubes, catheters for giving transfusions, removing blood,supplying saline solution to the body, etc.

EXAMPLE 17 The procedure of Example 16 was repeated replacing theethylene glycol dimethacrylate by an equal weight of divinyl benzene.The resulting syrup was equally use ful for coating ureteral andcannulae catheters with the syrup of Example 16.

EXAMPLE 1 8 A rubber Foley catheter was immersed in the casting syrup ofExample 8 and then removed and subjected to a temperature of 80 C. in aninert atmospheric to effect polymerization of the coating thus applied.The coated catheter was then immersed in an aqueous solution of neomycinsulfate (25 grams per 100 ml. of water) and then dried to provide acatheter effective in preventing infections when used in the urinarytract.

EXAMPLE 19 A No. 24 natural rubber Foley catheter having a weight of16.55 grams was wiped with xylene and immersed tip down in the syrup ofExample 16 to a depth of within 2 inches of the valve branch. Thecatheter was removed, allowed to drain 5 minutes, and the coating thuswas cured in an oven at 275 F. (134 C.) for minutes. The catheter thenweighed 16.71 grams, or exhibited a gain in weight of 0.16 gram. Thecatheter was then dipped into the syrup a second time, drained 5 minutesand cured at 275 F. for 15 minutes. The weight increased to 16.88 gramsfor an overall coating weight of 0.33 gram. After 30 seconds immersionin water, the coating was tough, flexible and strongly adherent to therubber substrate.

Obviously the dipping can be repeated 2, 3, 4, 5 or more times to buildup the thickness of the hydrophilic coating.

EXAMPLE The procedure of Example 19 was repeated using the casting syrupof Example 17 to give a coated Foley catheter.

6 EXAMPLE 21 The procedure of Example 19 was repeated using a No. 16Foley catheter. The catheter before coating weighed 11.70 grams andweighed 11.90 grams after coating.

EXAMPLE 22 A solution of 10 grams of cephalothin (Keflin, Lilly) in 40ml. of water was prepared. The catheter coated in accordance withExample 21 was immersed in the antibiotic solution for 10 minutes,removed, wiped free of surface moisture and weighed. A weight gain of0.42 gram was obtained. After drying, a net weight gain of 0.09 gram wasrecorded, indicating a pickup of mg. of the antibiotic.

This catheter when hydrated and inserted in the urethra and bladder of amale patient resulted in suppression of the bacteria content of theurine for a 7 day period after insertion.

EXAMPLE 23 Example 22 was repeated using a 10 gram solution of neomycinsulfate in 40 ml. of water in place of the cephalothin solution.Equivalent results were obtained.

EXAMPLE 24 Example 22 was repeated using Bacitracin in place of thecephalothin with equivalent results.

The use of the hydrophilic polymer permits the slow release of theantibiotic or germicide when such compounds are used to impregnate thehydrophilic polymer coating.

What is claimed is:

1. A process of preparing a flexible ureteral, urethral or cannulaeinfection preventing tubular catheter made of natural or syntheticrubber or flexible polyvinyl chloride having an adherent solid externalcoating of a polymeric compound of the group consisting of hydrophilicacrylate and methacrylate polymers comprising applying a liquid castingsyrup coating of the hydrophilic acrylate or methacrylate to thecatheter and then completing the polymerization of the hydrophilicacrylate or methacrylate to form a solid coating.

2. A process according to claim 1 wherein the polymeric compound isselected from the group consisting of polymers of hydroxy lower alkylacrylates, hydroxy lower alkyl methacrylates, hydroxy lower alkoxy loweralkyl acrylates, and hydroxy lower alkoxy lower alkyl methacrylates.

3. A process according to claim 2 wherein the catheter is made of rubberand the coating is allowed to swell the rubber prior to completing thepolymerization.

4. A process according to claim 3 wherein the coating liquid includes acopolymerizable polyethylenically unsaturated monomer in an amount of0.1 to 2.5% as a cross-linking agent.

5. A process according to claim 4 wherein a second liquid coating of ahydrophilic acrylate or methacrylate is applied over the first solidcoating and is then polymerized to form a solid coating thereon.

6. A process according to claim 5 wherein the second coating is the samehydrophilic polymer as the first coatmg.

7. A process according to claim 6 wherein the second coating is adifferent hydrophilic polymer from that of the first coating.

8. A process of preparing a coated catheter according to claim 2 havingan antibiotic or germicide in the coating comprising immersing the solidcoated catheter into a liquid solution of an antibiotic or germicide toobtain a catheter having said solid coating impregnated with saidantibiotic or germicide.

9. A process according to claim 8 including the additional step ofdrying the catheter whereby the liquid of said solution is removed butthe antibiotic or germicide is retained in the hydrophilic polymer.

10. A process according to claim 2 wherein the polymerization iscompleted by heating.

11. A process of adhering a compound of the group consisting ofhydrophilic acrylates and methacrylates to a rubber substrate comprisingswelling the rubber with a liquid casting syrup mixture of said acrylateor methacrylate and a minor amount up to 20% of a copolymerizablepolyethylenically unsaturated compound as a cross-linking agent and thencompleting the polymerization to form a solid adherent coating on saidrubber substrate.

12. A process according to claim 11 wherein the polymeric compound isselected from the group consisting of polymers of hydroxy lower alkylacrylates, hydroxy lower alkyl methacrylates, hydroxy lower alkoxy loweralkyl acrylates, and hydroxy lower alkoxy lower alkyl methacrylates.

13. A process according to claim 12 wherein the polymerization iscompleted by heating.

14. A process according to claim 12 wherein the rubber is naturalrubber.

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